Citalopram is an antidepressant drug that is widely used in both the United States and Europe. Its mode of action and activity have been described in various publications. The active ingredient is an HBr or oxalate salt, preferably an HBr salt. Citalopram has the following structure: 
Several processes have been described in the literature for preparing Citalopram (see, Drugs of Future, 25(6):620 (2000). Citalopram was first disclosed in German Patent 2,657,271, which is the German equivalent of now expired U.S. Pat. No. 4,136,193. In this patent, 5-bromophthalide (5-BP) was converted via a five-step reaction sequence to Citalopram. This route for preparing Citalopram is depicted in FIG. 1, and constitutes the basis of several patents and patent applications.
Attempts to reproduce the process described in U.S. Pat. No. 4,136,193 for the preparation of Citalopram in the quality specifications required for its use in pharmaceutical applications have been unsuccessful. It is noted that the quality specifications for pharmaceutical quality Citalopram are extremely stringent and require material with purity in excess of 99.7%. Difficulty encountered in manufacturing Citalopram of the required purity by the process described in German Patent No. 2,657,013, U.S. Pat. No. 4,136,193 and PCT International Publication Nos. WO 00/11926 and WO 00/13648 was recently described by Lundbeck in WO 01/45483 A2 (see, page 2, line 26).
Following is the detailed description of the process described in U.S. Pat. No. 4,136,193. It is noted that the experimental process described in U.S. Pat. No. 4,136,193 is for the 4-chlorophenyl analog, but it is noted therein that the process is applicable to the 4-fluorophenyl derivative as well. As illustrated in FIG. 1, the process described in U.S. Pat. No. 4,136,193 involves a 5-step conversion of 5-bromophthalide to Citalopram.
In the first step, a compound of Formula I (“5-BP”) is reacted with p-fluorophenyl-magnesium halide; in the second step, the intermediate of a compound of Formula II is isolated and reacted with N,N-dimethylaminopropylmagnesium halide to give the diol of Formula III (“Br-Diol”). The Grignard reaction is conducted in traditional solvents, such as diethyl ether and THF. Unfortunately, the work-up is very complex and involves excessive handling of a flammable liquid, i.e., diethyl ether. The work-up involves the following steps:                The reaction mixture is quenched into ice water;        An aqueous saturated ammonium chloride solution is added;        The mixture is extracted with diethyl ether;        The ether phase is then extracted with 20% aqueous acetic acid;        The acid phase is made alkaline with 10 N aqueous sodium hydroxide;        The aqueous phase is extracted with diethyl ether (2×);        The combined ethereal extracts are dried over anhydrous K2CO3;        The ether extract is treated with activated carbon; and        The solvent is evaporated in vacuum to give Br-Diol, an oil.        
The above work-up process is very laborious and is not suited for large-scale production. Again, it involves the excessive handling of flammable solvents, such as diethyl ether, and it involves numerous unit operations, thereby reducing productivity. Moreover, it is noted that Br-Diol is isolated as the free amine and is an oil. The physical characteristics of Br-Diol are important. Since Br-Diol is an oil, it cannot be isolated as a crystalline solid and, thus, it cannot be purified by techniques such as crystallization/recrystallization. Purification of this oil by crystallization or similar techniques is not described. It is believed that this is one of the major reasons why the process described in U.S. Pat. No. 4,136,193 fails to provide Citalopram in the quality, i.e., purity, required for drug applications. In addition, in order to meet the tight specifications for Citalopram, it is critical that purity is established at this stage.
In step three, Br-Diol is subjected to a ring closure reaction with 60% aqueous phosphoric acid. In a typical reaction, 5-bromophthalide is heated with excess (30 equivalents) 60% aqueous phosphoric acid for 3 h and then neutralized with saturated aqueous ammonia. The resulting mixture is then extracted with diethyl ether, and the ether extract is dried over potassium carbonate. The ether extract is then treated with activated charcoal and stripped of solvent under reduced pressure to give the compound of Formula IV (“5-Br”).
As mentioned above, step three employs a large excess of 60% aqueous phosphoric acid. This is troublesome because on reaction completion excess phosphoric acid has to be neutralized with ammonia. Neutralization is an extremely exothermic process and heat management becomes a major issue in the commercial-scale production of this material. In addition, the use of such a large excess of phosphoric acid increases the cost of commercial scale operations due to the use of excess reagents, longer cycle times and reduced loading. Moreover, from a safety point of view, the use of flammable solvents, such as diethyl ether, is discouraged for the commercial-scale production of organic compounds.
In step four, 5-Br is reacted with cuprous cyanide in DMF to give, after the work-up, Citalopram. The reaction conditions and work-up for the process described in U.S. Pat. No. 4,136,193 is as follows:                5-Br is reacted with CuCN in DMF at reflux for 4 h;        The reaction mixture is cooled to 55° C. and quenched into an aqueous solution of ethylene diamine;        The oily layer is separated and the aqueous layer is extracted with benzene;        The combined organic phases are washed with 10% aqueous sodium cyanide;        The organic layer is dried, treated with activated carbon, and concentrated under vacuum to give an oil;        The oil is dissolved in ether and extracted with aqueous acetic acid;        The acetic acid layer is made alkaline with 10 N aqueous sodium hydroxide and extracted with ether; and        The ethereal extract is dried over K2CO3, treated with activated charcoal, and stripped of solvent to give Citalopram.        
Unfortunately, there are numerous problems with step four. First, the reaction does not go to completion in 4 h; in reality, conversion after 4 h is <10%. Removal of unreacted 5-Br is difficult and normal purification techniques, such as extraction, crystallization, etc., are not effective. When the reaction is pushed to achieve higher conversion, formation of numerous unidentified side-products is observed. In short, the process described in U.S. Pat. No. 4,136,193 does not work to provide acceptable quality Citalopram. Moreover, the work-up is laborious and involves the use of undesirable solvents such as benzene and diethyl ether.
In the fifth and final step of the process described in U.S. Pat. No. 4,136,193, Citalopram is converted to Citalopram.HBr or the oxalate salt in the conventional manner—a process is not described for this conversion.
Another route for the preparation of Citalopram has been described in U.S. Pat. No. 4,650,884. This process is based on 5-cyanophthalide (“5-CN”). In this process, 5-CN is reacted with 4-fluorophenylmagnesium halide and N,N-dimethylaminopropylmagnesium halide to give the corresponding hydroxy intermediate that is then dehydrated with sulfuric acid to give Citalopram.
Although a number of processes have been described for the preparation of Citalopram, there remains a need in the art for additional processes that can be prepared in high yield, at the quality specifications required for use in pharmaceutical applications and without the limitations of the prior art method disclosed in now expired U.S. Pat. No. 4,136,193. Quite surprisingly, the present invention fulfills these and other needs.